This invention relates to a process for the preparation of anti-ischemic and anti-hypertensive amlodipine besylate.
Amlodipine besylate [2-{(2-aminoethoxy)]-methyl-4-(2-chlorophenyl)3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate] is a 1,-4-dihydro pyridine based derivative with potent calcium antagonist and vasodilator properties because of which it is an important drug in the treatment of angina and hypertension. It is of the formula I 
Amlodipine {2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} and its salts were first reported in European Patent No B10089167 which describes preparation of amlodipine and other 1,4-dihydro pyridine compounds from precursors such as phthalimido derivatives without purification. The precursors are corresponding azido derivatives produced by converting amino group by reduction either with Zn/HCl or by hydrogenation over palladium catalyst.
European Patent No B1-0244944 (U.S. Pat. No. 4,879,303) describes preparation of Amlodipine besylate by reacting amlodipine in its free base form with benzene sulfonic acid or ammonium benzene sulfonate an inert solvent such as industrial methanol at 5xc2x0 C. temperature.
European Patent No 599220 (U.S. Pat. Nos. 5,389,654 and 5,438,145) discloses a process for the preparation of amlodipine benzene sulfonate by reacting trityl-protected amlodipine base with benzene sulfonic acid in a methanolic or an aqueous methanolic medium at 20xc2x0 C. to reflux temperature. The amlodipine besylate formed is isolated and purified.
European Patent No 0902016 (U.S. Pat. No. 6,046,337) describes a process for the preparation of amlodipine besylate in which benzene sulfonic acid reacts with hexaminium iodide of amlodipine to form amlodipine besylate.
PCT Publication No WO 9952873 (European Patent No 0993447) describes a process for the preparation of amlodipine by reacting an inorganic acid with alkali metal benzene sulfonate in aqueous or alcohol water mixture.
PCT Publication No WO 01/02360 A1 describes a process for the preparation of amlodipine besylate by reacting N carboxy benzoyl derivative of amlodipine base with benzene sulfonic acid.
European Patent No 1125924 discloses a process for the synthesis of amlodipine, where in 3-amino-4-(2-phthalimido)ethoxy) crotonate is used as an intermediate.
Amlodipine besylate generally available contain impurities up to 0.3 to 0.8%. Such level of impurities is not desirable from pharmacological and toxicological considerations.
An object of this invention is to provide a process for the preparation of anti-ischemic and anti-hypertensive amlodipine besylate which is economical and easy to carry out.
Another object of this invention is to provide a process for the preparation of anti-ischemic and anti-hypertensive amlodipine besylate which is of high purity of the order of 99.9% in good yield.
Another object of this invention is to provide a process for the preparation of anti-ischemic and anti-hypertensive amlodipine besylate which is commercially viable.
According to the invention there is provided a process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate 2-{(2-aminoethoxy)-methyl-4 (2-chlorophenyl)3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate] of the formula I 
comprising:
(a) condensation of phthalic anhydride of the formula II 
with monoethanol amine at 150-190xc2x0 C. to form N-(2-hydroxyethyl)phthalimide of the formula III 
(b) coupling the compound of the formula III with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at xe2x88x9211 to xe2x88x9215xc2x0 C. to form ethyl-4-[-2(phthalimido) ethoxy] acetoacetate of the formula IV 
(c) coupling the compound of the formula IV with orthochloro benzaldehyde in the presence of pyridine salt at 70-90xc2x0 C. to form ethyl-2-(2-chloro benzylidine) 4-[-2(phthalimido)ethoxy] acetoacetate of the formula V 
(d) condensing the compound of the formula V with methyl amino crotonate at 20-40xc2x0 C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2-Phthalimidoethoxy) methyl-3-carboethoxy 1(chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] of the formula VI 
(e) purifying the compound of the formula VI by dissolving it in an organic solvent in the ratio 1:2-1:5 w/v followed by precipitation by the addition of water at 35-60xc2x0 C.;
(f) hydrolysing the purified compound of the formula VI with methylamine in the presence of a protic solvent at 20-50xc2x0 C. to form amlodipine base [2-(aminoethoxy)methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] of the formula VII 
(g) reacting the amlodipine base of the formula VII with benzene sulfonic acid to form the amlodipine besylate; and
(h) purifying the amlodipine besylate by dissolving it in an organic solvent at 30-70xc2x0 C. and precipitating it by the addition of an insoluble solvent.
According to the invention there is provided a process for the preparation of amlodipine besylate which employs inexpensive solvents and reagents and is, therefore, economical.
The reaction conditions of the invention are simple to follow. Therefore, it is easy to carry out. Besides, amlodipine besylate is obtained in very high purity of the order of 99.9% by the steps of purification of the intermediate phthaloyl amlodipine followed by hydrolysis in protic solvent and purification of the amlodipine besylate. For the above reasons, the process of the invention is commercially viable.
Purification of phthaloyl amlodipine is preferably carried out by dissolving it in an organic solvent in the ratio of 1.2 to 1.5 w/v at 40-60xc2x0 C. The organic solvent used for purification of phthaloyl amlodipine may be selected from acetone, methanol, denatured spirit, isopropyl alcohol, 1,4 dioxane or dimethyl formamide, preferably acetone.
Hydrolysis of phthaloyl amlodipine to amlodipine is carried out with a protic solvent such as ethanol, denatured spirit, methanol, isopropyl alcohol, chloroform or dioxane, preferably denatured spirit. The hydrolysis may be preferably carried out at room temperature.
Purification of amlodipine besylate is carried out in an organic solvent such as methanol, ethanol or chloroform, preferably methanol or chloroform. Purification of amlodipine besylate is carried out preferably at 65xc2x0 C.
Precipitation of amlodipine besylate is carried out using an insoluble solvent (i.e. a solvent in which amlodipine is insoluble) such as water, isopropyl alcohol or butanol, preferably isopropyl alcohol.